Intranasal drug administration has been shown to be an effective non-invasive route of administration for systemic drug delivery. Interestingly, individuals who consume illicit drugs have long ago adopted this route of administration. Although some evidence exists that substances may enter the brain directly from the nasal cavity, little attention has been paid to addressing the possibility that nasally applied abuse substances could be transported directly from the nasal cavity to the central nervous system (CNS). It is not clear whether direct entry of abused substances from the nasal cavity to the brain could result in more intense (CNS) drug exposure and increase abuse potential of neurologically active drugs. Furthermore, the blood-brain barrier represents one of the essential obstacles for using neuropeptides for the pharmacological treatment of central nervous diseases. Limited attention has been paid to the use of a nose-brain transport pathway to circumvent this problem in CNS peptide delivery. The overall objectives of the proposed research are to examine the significance of the direct nose-brain transport pathway for nasally applied drugs/peptides and to determine the effects of localized vasoconstriction on the extent of such transport. The proposed research is designed to examine two hypotheses: first, drugs/peptides can be transported directly from the nasal cavity to the brain; second, the extent of nose-brain drug transport is improved when the blood vessels in the nasal cavity are constricted. Specifically, the proposed research will employ rats as the animal model. Plasma and brain pharmacokinetic determinations will be used as a tool to determine whether nasally applied cocaine and an opioid can be transported directly from the nasal cavity to the brain. Studies are also designed to determine the effect of local vasoconstricting agents on the extent of nose-brain drug/peptide transpost. The long-term goals of the research are to determine the mechanisms responsible for direct nose-brain drug/peptide transport, to determine the phamacological and toxicological consequences of such transport, and to examine the utility of this novel pathway for brain delivery of neuroactive peptides/proteins/gene therapy vectors which have limited passage through the blood brain barrier.